A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.     

MYC amplification and polysomy 8 in chondrosarcoma: array comparative genomic hybridization, fluorescent in situ hybridization, and association with outcome.

PURPOSE: To identify recurrent regions of genomic gain or loss in chondrosarcoma in a clinically relevant and statistically valid fashion. Materials and METHODS: Array comparative genomic hybridization (CGH) results of 15 frozen tumor samples of high-grade chondrosarcoma for chromosome 8 are presented. A separate subset of 116 cartilaginous tumors with outcome data was used for validation. RESULTS: Array CGH identified gain at 8q24.12-q24.13, the region of the MYC (c-Myc) oncogene, as a frequent change in high-grade chondrosarcoma. In the validation arm of 116 cartilaginous tumors, MYC was frequently amplified in G2 (15%), G3 (20%), and dedifferentiated (21%) chondrosarcomas. No amplification was identified in samples of enchondroma and grade 1 chondrosarcoma. In samples without MYC amplification, polysomy 8 was a frequent finding in grade 1 (18%), grade 2 (31%), grade 3 (80%), and dedifferentiated (29%) chondrosarcomas, but was not found in any samples of enchondroma. MYC protein expression was identified in all samples with amplification, but was also frequent in the remaining samples without amplification or polysomy 8. Kaplan-Meier survival curves for overall survival showed a statistically significant difference for patients with MYC amplification or polysomy 8 (P = .034). Univariate analysis involving Cox proportional hazards models showed that grade (P = .003), polysomy 8 (P = .045), and MYC amplification (P = .053) correlated with shorter overall survival. By multivariate analysis, grade of chondrosarcoma (P = .026) was the only factor to reach statistical significance. CONCLUSION: MYC amplification and polysomy 8 can be used as markers of prognostic importance in chondrosarcoma. Molecular targeting of MYC expression may have therapeutic potential in the future for subsets of chondrosarcoma.     

ROLE OF INTERMEDIARY BIOMARKERS IN DETERMINING THE ANTICANCER EFFICACY OF MARINE COMPOUNDS

In the present study, two of the probable an umor marine compounds, manzamine A and sarcophine, were screened using benzo[a]pyrene (BP)-derived DNA adduct formation in MCF-7 cells as intermediary biomarker. Briefly, MCF-7 cells were treated with the compounds for 24 h followed by treatment with BP (0.5 μM). After 24h incubation, cellular DNA was isolated and analyzed for BP-derived DNA adducts by ³²P-postlabeling technique. Manzamine A and sarcophine increased the BP-DNA adducts by 2 to 4-folds. Further, manzamine A (50 μM) substantially down regulated the expression of p53 while sarcophine (50 μM) slightly induced the level of p21. The residual DNA repair ability was almost completely abolished by manzamine A while sarcophine was ineffective. Based on our preliminary results, these compounds may be classified as potential genotoxic.     

Head and facial injuries due to cluster munitions

Cluster munitions are weapons that scatter smaller sub-munitions intended to kill or mutilate on impact. They have been used by the Israeli army in the south of Lebanon and are now scattered over wide rural areas affecting its inhabitants. Because of their easily “pickable” nature, sub-munitions can inflict injuries to the head and face regions. In this study, we aimed to explore the head and face injuries along with their clinical features in a group of Lebanese patients who suffered from such injuries due to a sub-munition’s detonation. The study included all the cases reported between 14 August 2006 and 15 February 2013, with head and face injuries related to cluster bombs. Injuries were classified into brain, eye, otologic and auditory impairments, oral and maxillofacial, and skin and soft-tissue injuries. Psychological effects of these patients were also examined as for post-traumatic stress disorder, major depressive disorder, generalized anxiety disorder and acute stress syndrome. During the study period, there were 417 casualties as a result of cluster munitions’ blasts. Out of the total number of victims, 29 (7 %) were injured in the head and the face region. The convention on cluster munitions of 2008 should be adhered to, as these inhumane weapons indiscriminately and disproportionately harm innocent civilians, thereby violating the well-established international principles governing conflict and war today.     

Modifiable Factors to Decrease the Cost of Robotic-Assisted Procedures

In 2000, the US Food and Drug Administration approved the da Vinci Surgical System® for use in the United States. Since that time, the number of surgical robotic systems throughout the United States has continued to grow. The costs for using the system include the initial purchase ($1 million to $2.3 million) plus annual maintenance fees ($100,000 to $150,000) and the cost of limited-use or disposable instruments. Increasing the number of procedures that are performed using the robotic system can decrease the per-procedure costs. Two modifiable factors that contribute to increasing the annual caseload are increasing the number of surgeons capable of using the system and having a properly educated perioperative nursing team. An educated surgical team decreases turnover time, facilitates proper flow of each surgical procedure, and is able to actively and passively solve intraoperative problems.     

The effect of near‐peer tutoring on medical students' performance in anatomical and physiological sciences

Healthcare professional schools across the world are implementing near‐peer tutoring (NPT) programs owing to numerous benefits to both tutors and tutees. This study determined whether higher attendance at NPT sessions led to improvements in course grades for high and low performing students. Fourth‐year medical students used the USMLE Step 1 question format to tutor first‐year medical students during the second half of the Structure and Function (SF) module, i.e., SF2. Attendance was recorded and students were accordingly divided into three groups: high, moderate, and low‐no attendance. Students’ performances in SF1 and SF2 were compared using Student's t‐test. Differences among the three groups were analyzed using ANOVA and Scheffé post hoc test (P< 0.05). Students who earned 70–79% (C) in SF1 were further examined on the basis of their attendance rate and performance in SF2. Those who attended three or more sessions completed a survey evaluating the NPT program. Course grades were significantly higher in SF2 than SF1 for all students, regardless of attendance rate. However, students who received a C grade in SF1 and had high or moderate attendance improved significantly in their SF2 course grade. Most students agreed that the NPT program was valuable and they evaluated the tutors highly. They also agreed that NPT prepared them for course exams and Step 1, but did not reduce anxiety and stress about Step 1. The positive effect of the NPT program resulted in its expansion to include all first‐year modules. Clin. Anat. 30:922–928, 2017. © 2017 Wiley Periodicals, Inc.     

Systematic review of the outcome associated with the different surgical treatment of bowel and rectovaginal endometriosis

Background: Treatment of deep endometriosis involving the bowel is controversial. There is limitation of medical treatment. Several surgical techniques are used. All of them are associated with potential intraoperative complications and long-term hazards for the bladder, bowel and sexual function. Objectives: This study seeks to review systematically different types of surgical treatment of bowel endometriosis which include mucosal skinning (shaving), disc excision, and segmental resection. The review includes the number of participants, histology, symptomatology, preoperative assessment, types and access of surgery, complications, hospital stay, length and way of follow up, symptom improvement, recurrence, and effects on fertility. Study strategy: All published articles on surgical treatment of endometriosis (shaving, rectovaginal endometriosis, disc excision, and segmental resection), identified through MEDLINE, EMBASE, CINAHL, and Cochran library during 1970–2011. Grey literatures were searched as well. Selection criteria: The terms ‘endometriosis’, ‘bowel’, surgical, and complications were used. Articles describing 50 patients or more who had bowel surgery for endometriosis were only included. Data collection and analysis: Data did not permit a meaningful meta-analysis. Main results: We analyzed 36 articles after thorough literature search. It described 2,414 of mucosal skinning/rectovaginal endometriosis, 381 of disc excision, and 2,728 of bowel resection for deep endometriosis involving the bowel. The indication for surgery was stated in most of the studies. Histology was confirmed in the majority; however, completeness of the excision was stated in few articles. There is significant improvement of symptoms with all types of surgery. Complications were higher in segmental resection than conservative surgery (shaving and disc excision) especially leakage and fistula formation. The duration of surgery and hospital stay was shorter in conservative surgery unless there were complications or if associated with other surgeries. Fertility outcome was favourable in all. The recurrence and reoperation rate was higher in one study only in the shaving group, but otherwise was comparable to the resection group. Conclusion: There was no difference in the outcome between different types of surgery which indicates that we should adopt the conservative surgery if possible. The heterogeneity of the studies makes it difficult to do any valuable statistical analysis. There should be standardization in clinical trials evaluating bowel surgery for endometriosis.